Alzheimer's amyloid β heterogeneous species differentially affect brain endothelial cell viability, blood-brain barrier integrity, and angiogenesis.
Alzheimer's amyloid β heterogeneous species differentially affect brain endothelial cell viability, blood-brain barrier integrity, and angiogenesis.
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阿尔茨海默氏症的淀粉样β异质物种差异地影响了脑内皮细胞活力，血脑屏障完整性和血管生成。
DOI：
10.1111/acel.13258
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发表时间：
2020-11
期刊：
影响因子：
7.8
通讯作者：
Fossati S
中科院分区：
文献类型：
--
作者：
Parodi-Rullán R;Ghiso J;Cabrera E;Rostagno A;Fossati S
阿尔茨海默病（AD）大脑中的清除率受损是Aβ实质斑块和脑血管沉积物（称为脑淀粉样血管病（CAA））形成的关键，存在于>80%的AD患者和约50%的非AD老年受试者中。Aβ沉积物具有高度异质性，包含多个主要来自Aβ40/Aβ42催化剂的片段，这些片段表现出不同的聚集特性。值得注意的是，这些生理学相关的Aβ物质在脑血管损伤中的作用及其对血管病理学的影响尚不清楚。我们试图了解异质性Aβ物质如何影响脑内皮健康，并评估其不同效应是否与肽聚集倾向相关。我们分析了脑微血管内皮细胞（CMEC）活力、血脑屏障（BBB）通透性和血管生成，以及脑微血管功能障碍的所有相关方面。我们发现Aβ肽和片段对脑血管病理学的影响不同。肽形成主要是寡聚体结构诱导CMEC凋亡，而纤维状聚集体增加血脑屏障通透性没有凋亡作用。有趣的是，所有测试的Aβ物质都在体外抑制血管生成。这些数据将异质性Aβ肽的生物学效应与其一级结构和聚集联系起来，强烈表明淀粉样蛋白沉积物的组成影响AD血管病理学的临床方面。由于血管壁附近主要寡聚体结构的存在可能导致CMEC死亡和微血管形成的诱导，纤维状淀粉样蛋白可能是BBB通透性增加和相关神经血管功能障碍的原因。这些结果有可能揭示更具体的治疗靶点，并澄清AD的多因素性质。本研究表明，全长Aβ肽、截短Aβ片段和亲血管性Aβ变体对微血管内皮细胞功能的影响与其聚集特性有关。了解这些对单独但相互关联的脑血管变性途径的影响，如BBB通透性，EC凋亡和血管生成，将为AD和血管性痴呆的病理学和不同临床亚型提供新的见解。
Impaired clearance in the Alzheimer's Disease (AD) brain is key in the formation of Aβ parenchymal plaques and cerebrovascular deposits known as cerebral amyloid angiopathy (CAA), present in >80% of AD patients and ~50% of non‐AD elderly subjects. Aβ deposits are highly heterogeneous, containing multiple fragments mostly derived from catabolism of Aβ40/Aβ42, which exhibit dissimilar aggregation properties. Remarkably, the role of these physiologically relevant Aβ species in cerebrovascular injury and their impact in vascular pathology is unknown. We sought to understand how heterogeneous Aβ species affect cerebral endothelial health and assess whether their diverse effects are associated with the peptides aggregation propensities. We analyzed cerebral microvascular endothelial cell (CMEC) viability, blood‐brain barrier (BBB) permeability, and angiogenesis, all relevant aspects of brain microvascular dysfunction. We found that Aβ peptides and fragments exerted differential effects on cerebrovascular pathology. Peptides forming mostly oligomeric structures induced CMEC apoptosis, whereas fibrillar aggregates increased BBB permeability without apoptotic effects. Interestingly, all Aβ species tested inhibited angiogenesis in vitro. These data link the biological effects of the heterogeneous Aβ peptides to their primary structure and aggregation, strongly suggesting that the composition of amyloid deposits influences clinical aspects of the AD vascular pathology. As the presence of predominant oligomeric structures in proximity of the vessel walls may lead to CMEC death and induction of microhemorrhages, fibrillar amyloid is likely responsible for increased BBB permeability and associated neurovascular dysfunction. These results have the potential to unveil more specific therapeutic targets and clarify the multifactorial nature of AD. This study demonstrates that full length Aβ peptides, truncated Aβ fragments, and vasculotropic Aβ variants, differentially impact microvascular endothelial cell function, in relation to their aggregation properties. Understanding these effects on separate but interconnected cerebrovascular degeneration pathways, such as BBB permeability, EC apoptosis and angiogenesis, will provide new insights into the pathology and different clinical subtypes of AD and vascular dementia.
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影响因子：
12.7
作者：
Bouter Y;Dietrich K;Wittnam JL;Rezaei-Ghaleh N;Pillot T;Papot-Couturier S;Lefebvre T;Sprenger F;Wirths O;Zweckstetter M;Bayer TA
通讯作者：
Bayer TA
影响因子：
3.7
作者：
Biron KE;Dickstein DL;Gopaul R;Jefferies WA
通讯作者：
Jefferies WA
DOI：
10.3233/jad-140027
发表时间：
2014
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Ghiso J;Fossati S;Rostagno A
通讯作者：
Rostagno A
影响因子：
4.8
作者：
Fossati, S.;Cam, J.;Rostagno, A.
通讯作者：
Rostagno, A.
DOI：
10.1016/j.bbadis.2017.07.005
发表时间：
2018-01
期刊：
Biochimica et biophysica acta. Molecular basis of disease
影响因子：
--
作者：
Cabrera E;Mathews P;Mezhericher E;Beach TG;Deng J;Neubert TA;Rostagno A;Ghiso J
通讯作者：
Ghiso J